2.1. Stereochemistry
The study of the spatial arrangement of atoms in a compound and their relation to the properties of the compound is called stereochemistry. Stereoisomers are molecules which possess identical chemical formulas with the same atoms bonded to one another, however they differ in the manner in which these atoms are arranged in three dimensional space. Optical isomers or enantiomers are molecules that are mirror images but are nonetheless nonsuperimposable. Such molecules can rotate the plane of plane-polarized light. Molecules that exhibit this phenomenon are said to be optically active. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). A chiral center is usually an asymmetric carbon atom, that is, one with four different groups attached to it. The prefixes (+) and (-) or d and l are employed to designate the sign of rotation of plane-polarized light by the compound. A compound with the prefix (-) or l is levorotatory. A levorotatory compound rotates plane-polarized light to the left (counterclockwise). A compound prefixed with (+) or d is dextrorotatory. A dextrorotatory compound rotates plane polarized light to the right (clockwise). As mentioned above, a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
The property of optical activity is due to molecular asymmetry about carbon atoms that are linked to four different atoms. Where there is only one asymmetric carbon atom, or chiral center as it is sometimes called, there are two possible stereoisomers. Where there are n asymmetric carbons or chiral centers, the number of potential stereoisomers increases to 2.sup.n. Thus, a molecule with three chiral centers would have eight possible stereoisomers.
While the structural differences between stereoisomers are subtle and of little consequence in ordinary chemical reactions, they may be profound where biological systems are concerned, i.e., if the compounds are utilized in enzyme-catalyzed reactions. Thus, the L-amino acids are metabolized in humans but the corresponding D-analogs are not, and only D-glucose can be phosphorylated and processed into glycogen or degraded by the glycolytic and oxidative pathways or intermediary metabolism. Similarly, beta blockers, pheromones, prostaglandins, steroids, flavoring and fragrance agents, pharmaceuticals, pesticides, herbicides and many other compounds exhibit critical stereospecificity. In the field of pesticides, Tessier (Chemistry and Industry, 1984, Mar. 19, 199) has shown that only two of the eight stereoisomers of deltamethrin, a pyrethroid insecticide, have any biological activity. The same statement concerning the concentration of bioactivity in a single isomer can be made about many other pesticides, including the phenoxypropionates and halopropionate derivatives, each containing one chiral center and existing in the form of two optical isomers.
Stereochemical purity is of equal importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by naproxen, or (+)-S-2-(6-methoxy-2-naphthyl)propanoic acid, which is one of the two most important members of a class of 2-arylpropanoic acids with non-steroidal anti-inflammatory activity used, for instance, in the management of arthritis. In this case, the S(+) enantiomer of the drug is known to be 28 times more therapeutically potent than its R(-) counterpart. Still another example of chiral pharmaceuticals is provided by the family of beta-blockers; the L-form of propranol is known to be 100 times more potent than the D-enantiomer.
Synthesis of compounds with asymmetric centers by standard organic synthetic techniques generally leads to a racemic mixture which, in the aggregate, may have a relatively low specific bioactivity since certain of the stereoisomers in the mixture are likely to be biologically or functionally inactive. As a result, larger quantities of the material must be used to obtain an effective dose, and manufacturing costs are increased due to the co-production of stereochemically "incorrect" and hence, inactive ingredients.
Thus, optical purity or enantiomeric excess is a very important consideration in the design of chemical syntheses of optically active compounds.